2. Academic Validation
  3. The APP intracellular domain promotes LRRK2 expression to enable feed-forward neurodegenerative mechanisms in Parkinson's disease

The APP intracellular domain promotes LRRK2 expression to enable feed-forward neurodegenerative mechanisms in Parkinson's disease

  • Sci Signal. 2022 Aug 23;15(748):eabk3411. doi: 10.1126/scisignal.abk3411.
Zhi-Wei Zhang 1,  Haitao Tu 1,  Mei Jiang 1 2,  Sarivin Vanan 1,  Sook Yoong Chia 1,  Se-Eun Jang 1,  Wuan-Ting Saw 3,  Zhi-Wei Ong 1,  Dong-Rui Ma 4,  Zhi-Dong Zhou 3 5,  Jie Xu 2,  Kai-Hua Guo 2,  Wei-Ping Yu 6 7,  Shuo-Chien Ling 5 8,  Richard A Margolin 9,  Daniel G Chain 9,  Li Zeng 1 5 10,  Eng-King Tan 3 5 11
Affiliations

Affiliations

  • 1 Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore.
  • 2 Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
  • 3 Research Department, National Neuroscience Institute, Singapore General Hospital (SGH) Campus, Singapore 169856, Singapore.
  • 4 Department of Neurology, Singapore General Hospital, Singapore 169609, Singapore.
  • 5 Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore.
  • 6 Animal Gene Editing Laboratory, Biological Resource Center, A*STAR, Singapore 138673, Singapore.
  • 7 Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore.
  • 8 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.
  • 9 CereSpir Incorporated, New York, NY 10010, USA.
  • 10 Centre for Molecular Neuropathology, Lee Kong Chian School of Medicine, Nanyang Technology University, Novena Campus, Singapore 308232, Singapore.
  • 11 Department of Neurology, National Neuroscience Institute, Singapore 308433, Singapore.
PMID: 35998231 DOI: 10.1126/scisignal.abk3411
Abstract

Gain-of-function mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are common in familial forms of Parkinson's disease (PD), which is characterized by progressive neurodegeneration that impairs motor and cognitive function. We previously demonstrated that LRRK2-mediated phosphorylation of β-amyloid precursor protein (APP) triggers the production and nuclear translocation of the APP intracellular domain (AICD). Here, we connected LRRK2 to AICD in a feed-forward cycle that enhanced LRRK2-mediated neurotoxicity. In cooperation with the transcription factor FOXO3a, AICD promoted LRRK2 expression, thus increasing the abundance of LRRK2 that promotes AICD activation. APP deficiency in LRRK2G2019S mice suppressed LRRK2 expression, LRRK2-mediated mitochondrial dysfunction, α-synuclein accumulation, and tyrosine hydroxylase (TH) loss in the brain, phenotypes associated with toxicity and loss of dopaminergic neurons in PD. Conversely, AICD overexpression increased LRRK2 expression and LRRK2-mediated neurotoxicity in LRRK2G2019S mice. In LRRK2G2019S mice or cultured dopaminergic neurons from LRRK2G2019S patients, treatment with itanapraced reduced LRRK2 expression and was neuroprotective. Itanapraced showed similar effects in a neurotoxin-induced PD mouse model, suggesting that inhibiting the AICD may also have therapeutic benefits in idiopathic PD. Our findings reveal a therapeutically targetable, feed-forward mechanism through which AICD promotes LRRK2-mediated neurotoxicity in PD.

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